In recent years, electron spin resonance (ESR) imaging by way of reactive oxygen species and radical species for tracing reactions in vitro and the use of stable radicals in the prevention, treatment or the like, of diseases or symptoms in which the reactive oxygen species are involved, have been drawing attention.
The ESR method has been used widely under in and ex vivo environments, using signal analysis and the spin trapping method, for L band ESR imaging, generation and annihilation of reactive oxygen species, and the like. Although the ESR-active electronic spin is known to be an extremely unstable reactive species, for stable cyclic nitroxide radicals such as the 2,2,6,6-tetramethylpiperidino oxy radical (TEMPO), the radical being stabilized, even more various applications are being developed, and in addition, examined (for instance, refer to Non-patent Reference 1 mentioned below). However, the current situation is that such stable cyclic nitroxide radicals are difficult to handle, as the radical or even the stable electronic spin is reduced in a short time in the presence of a reducing species such as ascorbic acid, which is present in vivo.
Note that one of the uses mentioned above, the so-called spin labeling method, is a method whereby stable nitroxide radicals are used as labeling agents for conjugation to proteins, fatty acids or steroids; however this is not intended to stabilize further the stable nitroxide radicals under an external environment, and no improved stabilization can be expected either. In addition, covalently bonding a plurality of stable nitroxide radicals, along with one or a plurality of metal ions/chelaters, to a polymer or an oligomer to try an add a novel function to an MRI contrast medium has also been proposed (for instance, refer to Patent Reference 1 mentioned below).
Meanwhile, it is also known that reactive oxygen species and reactive radical species play important roles in vivo. For instance, a free radical such as the hydroxy radical has been cited as one of the causes involved in the damage of a brain. Typically, it is known that free radicals tend to appear in the penumbra (ischemic penumbra) region, considered as the drug treatment region, during cerebral ischemia or after reperfusion. Therefore, some free radical scavengers have drawn attention as brain protecting agents that eliminate/render harmless a radical causing damages to brain vessels and neuronal cells, and as one among such scavengers, Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one) is sold commercially under the product name Radicut (refer to Non-patent Reference 2 mentioned below). However, it is also known that the use of Edaravone is accompanied by a risk of the adverse effect of acute kidney failure (kidney function disorder, liver function disorder and heart disease as complications). In addition, it is thought that there is room for improvement from the aspect of the effect and the aspect of safety, since in human, from the aspect of safety, Edaravone is administered multiple times by dividing into smaller amounts than the dose for which remarkable effects are observed in animal experiments.
In addition, it has been discovered that the cyclic nitroxide compounds classified in the above stable cyclic nitroxide radicals, 4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (Tempol) to begin with, which has unique antioxidant properties, have the ability to decompose a superoxide or a peroxide, thereby functioning as radical scavengers, altering oxidative stress and altering the redox state of a tissue, and thereby interacting with and then altering many metabolic processes (refer to Non-patent Reference 3 mentioned below). Then, in Non-patent Reference 3, it has been suggested that these interactions could be used in therapeutic and research applications including protection against ionizing radiations, probes for functional magnetic resonance imaging, prevention or treatment of cancer, regulation of hypertension and body weight, and defense against damages caused by ischemia and reperfusion. However, once they have entered inside an organism, cyclic nitroxide compounds no longer function as radical scavengers if they are reduced by an endogenous reducing agent such as ascorbic acid.
In prior art, the present inventors have shown that nanoparticles (or polymeric micelles) from the self-assemblage of hydrophylic-phobic type block copolymers in water function as novel materials enabling drug carriers and nano-diagnoses, and have moved various material designs forward. In particular, by introducing a functional group at the water-soluble macromolecular end of the hydrophylic-phobic block copolymer, core-shell type nanoparticles with tens of nanometers in size having a ligand insertion site on the surface layer hold expectations as novel drug carriers enabling active targeting (for instance, refer to Patent Reference 2 and Patent Reference 3 mentioned below).    Patent Reference 1: Japanese Translation of PCT Application No. 2001-523215 (or WO96/32967)    Patent Reference 2: WO96/33233 (or U.S. Pat. No. 5,925,720)    Patent Reference 3: WO97/06202 (or U.S. Pat. No. 5,929,177)    Non-patent Reference 1: B. P. Soule et al., Free Radical Biology & Medicine 42 (2007) 1632-1650    Non-patent Reference 2: J. Pharmacol. Exp. Ther. 281: 921-927, 1997    Non-patent Reference 3: James B. Mitchell, et al., Free Radical Biology & Medicine 42 (2007) 1632-650